We and others have shown that to initiate and maintain the growth and differentiation of primitive progenitor cells, multiple cytokine stimulation (synergy) is required. More recently, we showed that such cooperation also occurs between negative regulators of cell growth, and that the ability of primitive progenitors to proliferate depends on the balance of positive and negative signals the cell receives. Transforming growth factor beta (TGF?) directly and reversibly inhibits hematopoietic stem cells with marrow repopulating ability (LT-HSC). Also, short-term incubation with antibody and antisense to TGF? stimulates the self-renewal potential of these stem cells. TGF? has inhibitory effects on the cell surface expression of many cytokine receptors that directly correlates with its effect on cell growth. For example, stem cell factor receptor (c-kit) expression is downregulated by TGF?, in part by affecting c-kit mRNA stability. These results indicated that c-kit expression couldbe negatively regulated on LT-HSC. Indeed, we were able to characterize a novel LT-HSC lacking c-kit expression and that in bone marrow cell development, this cell matures into a c-kit+ LT-HSC. Also, TGF? prevents S phase cell-cycle progression through an intracellular mechanism involving regulation of transcription factors and cell-cycle regulatory proteins. In vivo results demonstrated that TGF? can protect mice from both the lethal hematopoietic toxicity of 5-FU, as well as the nonhematopoiesis toxicity of DXR. These findings show that a negative regulator of hematopoiesis can be successfully used systemically to mediate chemoprotection in vivo. Previous results from many labs also indicated that TGF? treatment of donor cells before bone marrow transplantation (BMT) could have a beneficial effect by blocking the immune reactivity. We were able to show suppression of graft vs host disease (GVHD) after allogeneic BMT through a TGF? mediated mechanism. Treatment of donor CD4 T-cells with TGF? and IL-10 made the donor T-cells hyporesponsive and less able to promote GVHD. In many instances, growth inhibition following terminal differentiation or anti-cancer drug treatment results in apoptosis (programmed cell death).

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009264-19
Application #
6762147
Study Section
(LLB)
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Birchenall-Roberts, Maria C; Fu, Tao; Kim, Soo-Gyung et al. (2006) K-Ras4B proteins are expressed in the nucleolus: Interaction with nucleolin. Biochem Biophys Res Commun 348:540-9
Jones, Kathryn S; Akel, Salem; Petrow-Sadowski, Cari et al. (2005) Induction of human T cell leukemia virus type I receptors on quiescent naive T lymphocytes by TGF-beta. J Immunol 174:4262-70
Ruscetti, Francis W; Akel, Salem; Bartelmez, Stephen H (2005) Autocrine transforming growth factor-beta regulation of hematopoiesis: many outcomes that depend on the context. Oncogene 24:5751-63
Birchenall-Roberts, Maria C; Fu, Tao; Bang, Ok-Sun et al. (2004) Tuberous sclerosis complex 2 gene product interacts with human SMAD proteins. A molecular link of two tumor suppressor pathways. J Biol Chem 279:25605-13
Akel, Salem; Petrow-Sadowski, Cari; Laughlin, Mary J et al. (2003) Neutralization of autocrine transforming growth factor-beta in human cord blood CD34(+)CD38(-)Lin(-) cells promotes stem-cell-factor-mediated erythropoietin-independent early erythroid progenitor development and reduces terminal differentiation. Stem Cells 21:557-67
Cao, Zhouhong; Flanders, Kathleen C; Bertolette, Daniel et al. (2003) Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells. Blood 101:498-507
Muegge, Kathrin; Young, Howard; Ruscetti, Francis et al. (2003) Epigenetic control during lymphoid development and immune responses: aberrant regulation, viruses, and cancer. Ann N Y Acad Sci 983:55-70